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| | ==TorsinA-LULL1 complex, H. sapiens, bound to VHH-BS2== | | ==TorsinA-LULL1 complex, H. sapiens, bound to VHH-BS2== |
| - | <StructureSection load='5j1s' size='340' side='right' caption='[[5j1s]], [[Resolution|resolution]] 1.40Å' scene=''> | + | <StructureSection load='5j1s' size='340' side='right'caption='[[5j1s]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5j1s]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J1S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J1S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5j1s]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Vicugna_pacos Vicugna pacos]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J1S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J1S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.399Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j1s OCA], [http://pdbe.org/5j1s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j1s RCSB], [http://www.ebi.ac.uk/pdbsum/5j1s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j1s ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5j1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j1s OCA], [https://pdbe.org/5j1s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j1s RCSB], [https://www.ebi.ac.uk/pdbsum/5j1s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j1s ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TOR1A_HUMAN TOR1A_HUMAN]] Myoclonus-dystonia syndrome;Early-onset generalized limb-onset dystonia. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/TOR1A_HUMAN TOR1A_HUMAN] Myoclonus-dystonia syndrome;Early-onset generalized limb-onset dystonia. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TOR1A_HUMAN TOR1A_HUMAN]] Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.<ref>PMID:15505207</ref> <ref>PMID:16361107</ref> <ref>PMID:17428918</ref> <ref>PMID:18167355</ref> <ref>PMID:18827015</ref> <ref>PMID:19339278</ref> <ref>PMID:20169475</ref> <ref>PMID:23569223</ref> [[http://www.uniprot.org/uniprot/TOIP2_HUMAN TOIP2_HUMAN]] Required for endoplasmic reticulum integrity. Regulates the distribution of TOR1A between the endoplasmic reticulum and the nuclear envelope as well as induces TOR1A, TOR1B and TOR3A ATPase activity.<ref>PMID:19339278</ref> <ref>PMID:23569223</ref> <ref>PMID:24275647</ref> | + | [https://www.uniprot.org/uniprot/TOR1A_HUMAN TOR1A_HUMAN] Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.<ref>PMID:15505207</ref> <ref>PMID:16361107</ref> <ref>PMID:17428918</ref> <ref>PMID:18167355</ref> <ref>PMID:18827015</ref> <ref>PMID:19339278</ref> <ref>PMID:20169475</ref> <ref>PMID:23569223</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5j1s" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5j1s" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| | + | *[[3D structures of non-human antibody|3D structures of non-human antibody]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Demircioglu, F E]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Schwartz, T U]] | + | [[Category: Large Structures]] |
| - | [[Category: Aaa+ atpase]] | + | [[Category: Vicugna pacos]] |
| - | [[Category: Endoplasmic reticulum]] | + | [[Category: Demircioglu FE]] |
| - | [[Category: Hydrolase]] | + | [[Category: Schwartz TU]] |
| - | [[Category: Torsin]]
| + | |
| Structural highlights
Disease
TOR1A_HUMAN Myoclonus-dystonia syndrome;Early-onset generalized limb-onset dystonia. The disease is caused by mutations affecting the gene represented in this entry.
Function
TOR1A_HUMAN Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
The most common cause of early onset primary dystonia, a neuromuscular disease, is a glutamate deletion (DeltaE) at position 302/303 of TorsinA, a AAA+ ATPase that resides in the endoplasmic reticulum. While the function of TorsinA remains elusive, the DeltaE mutation is known to diminish binding of two TorsinA ATPase activators: lamina-associated protein 1 (LAP1) and its paralog, luminal domain like LAP1 (LULL1). Using a nanobody as a crystallization chaperone, we obtained a 1.4 A crystal structure of human TorsinA in complex with LULL1. This nanobody likewise stabilized the weakened TorsinADeltaE-LULL1 interaction, which enabled us to solve its structure at 1.4 A also. A comparison of these structures shows, in atomic detail, the subtle differences in activator interactions that separate the healthy from the diseased state. This information may provide a structural platform for drug development, as a small molecule that rescues TorsinADeltaE could serve as a cure for primary dystonia.
Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia.,Demircioglu FE, Sosa BA, Ingram J, Ploegh HL, Schwartz TU Elife. 2016 Aug 4;5. pii: e17983. doi: 10.7554/eLife.17983. PMID:27490483[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Torres GE, Sweeney AL, Beaulieu JM, Shashidharan P, Caron MG. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15650-5. Epub 2004 Oct 25. PMID:15505207 doi:http://dx.doi.org/10.1073/pnas.0308088101
- ↑ Hewett JW, Zeng J, Niland BP, Bragg DC, Breakefield XO. Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. Neurobiol Dis. 2006 Apr;22(1):98-111. Epub 2005 Dec 19. PMID:16361107 doi:http://dx.doi.org/10.1016/j.nbd.2005.10.012
- ↑ Hewett JW, Tannous B, Niland BP, Nery FC, Zeng J, Li Y, Breakefield XO. Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7271-6. Epub 2007 Apr 11. PMID:17428918 doi:http://dx.doi.org/10.1073/pnas.0701185104
- ↑ Granata A, Watson R, Collinson LM, Schiavo G, Warner TT. The dystonia-associated protein torsinA modulates synaptic vesicle recycling. J Biol Chem. 2008 Mar 21;283(12):7568-79. doi: 10.1074/jbc.M704097200. Epub 2007 , Dec 31. PMID:18167355 doi:http://dx.doi.org/10.1074/jbc.M704097200
- ↑ Nery FC, Zeng J, Niland BP, Hewett J, Farley J, Irimia D, Li Y, Wiche G, Sonnenberg A, Breakefield XO. TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton. J Cell Sci. 2008 Oct 15;121(Pt 20):3476-86. doi: 10.1242/jcs.029454. Epub 2008, Sep 30. PMID:18827015 doi:http://dx.doi.org/10.1242/jcs.029454
- ↑ Vander Heyden AB, Naismith TV, Snapp EL, Hodzic D, Hanson PI. LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol Biol Cell. 2009 Jun;20(11):2661-72. doi: 10.1091/mbc.E09-01-0094. Epub 2009, Apr 1. PMID:19339278 doi:http://dx.doi.org/10.1091/mbc.E09-01-0094
- ↑ Burdette AJ, Churchill PF, Caldwell GA, Caldwell KA. The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro. Cell Stress Chaperones. 2010 Sep;15(5):605-17. doi: 10.1007/s12192-010-0173-2., Epub 2010 Feb 19. PMID:20169475 doi:http://dx.doi.org/10.1007/s12192-010-0173-2
- ↑ Zhao C, Brown RS, Chase AR, Eisele MR, Schlieker C. Regulation of Torsin ATPases by LAP1 and LULL1. Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):E1545-54. doi:, 10.1073/pnas.1300676110. Epub 2013 Apr 8. PMID:23569223 doi:http://dx.doi.org/10.1073/pnas.1300676110
- ↑ Demircioglu FE, Sosa BA, Ingram J, Ploegh HL, Schwartz TU. Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. Elife. 2016 Aug 4;5. pii: e17983. doi: 10.7554/eLife.17983. PMID:27490483 doi:http://dx.doi.org/10.7554/eLife.17983
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